Cyclopentanone derivatives

ABSTRACT

Cyclopentane derivatives of the formula: ##STR1## wherein R 1  represents hydrogen or a carboxylic acyl group, and either (I) R 2  represents a group of the formula: 
     
         --CR.sup.3 R.sup.4 R.sup.5                                 II 
    
     (wherein R 3  and R 4  represent hydrogen or alkyl, and R 5  represents hydrogen, or alkyl, alkoxy, cycloalkyl or adamantyl, or R 5  represents alkyl substituted by alkoxy, or by cycloalkyl or by adamantyl, or the group --CR 3  R 4  R 5  together forms a cycloalkyl or adamantyl group), X represents trans-vinylene or ethylene and Y represents carbonyl or a group of the formula: ##STR2## wherein R 6  represents hydrogen or alkyl, and R 7  represents hydrogen or a carboxylic acyl group, or else 
     (ii) R 2  represents a group of the formula: 
     
         --A-Z-R.sup.8                                              IV 
    
     (wherein A represents alkylene, Z represents a direct bond or oxygen or sulphur, and R 8  represents an aryl or heterocyclyl group which may be substituted by one or more of halogen, alkyl, alkoxy and trihalomethyl), X in formula I represents ethylene or trans-vinylene and Y in formula I represents carbonyl or a group of formula III, or else 
     (iii) R 2  represents a group R 8  and X and Y in formula I represent simultaneously ethylene and carbonyl, trans-vinylene and carbonyl, or ethylene and --CH(OR 7 )-- groups respectively. The compounds are new and possess pharmacological properties similar to those of prostaglandins.

This invention relates to new therapeutically useful cyclopentanederivatives, to a process for preparing them, and to pharmaceuticalcompositions containing them.

The new cyclopentane derivatives of the present invention are thosecompounds of the general formula: ##STR3## wherein R¹ represents ahydrogen atom or a carboxylic acyl group, preferably a straight- orbranched-chain alkanoyl group containing from 1 to 4 carbon atoms or abenzoyl group, and either

(I) R² represents a group of the general formula:

    --CR.sup.3 R.sup.4 R.sup.5                                 II

(wherein R³ and R⁴ are identical or different and each represents ahydrogen atom or a straight- or branched-chain alkyl group containingfrom 1 to 4 carbon atoms, for example a methyl group, R⁵ represents ahydrogen atom or, preferably, a straight- or branched-chain alkyl groupcontaining from 1 to 10, preferably from 1 to 5, more particularly 4,carbon atoms, a straight- or branched-chain alkoxy group containing from1 to 10, preferably from 1 to 4, carbon atoms, a cycloalkyl groupcontaining from 5 to 7 carbon atoms, an adamantyl group, or represents astraight- or branched-chain alkyl group containing from 1 to 6 carbonatoms, preferably methyl, substituted by a straight- or branched-chainalkoxy group containing from 1 to 6 carbon atoms, preferably ethoxy, bya cycloalkyl group containing from 5 to 7 carbon atoms or by anadamantyl group, or the group --CR³ R⁴ R⁵ together forms a cycloalkylgroup containing from 5 to 7 carbon atoms, preferably cyclopentyl orcyclohexyl, or an adamantyl group), X represents a trans-vinylene or anethylene group, and Y represents a carbonyl group or a group of thegeneral formula: ##STR4## wherein R⁶ represents a hydrogen atom or astraight- or branched-chain alkyl group containing from 1 to 4 carbonatoms, preferably methyl, and R⁷ represents a hydrogen atom or acarboxylic acyl group, preferably a straight- or branched-chain alkanoylgroup containing from 1 to 4 carbon atoms or a benzoyl group, or else

(ii) R² represents a group of the general formula:

    --A-Z-R.sup.8                                              IV

[wherein A represents a straight- or branched-alkylene chain containingfrom 1 to 12, preferably from 1 to 7 carbon atoms, Z represents a directbond or an oxygen or sulphur atom, and R⁸ represents an aryl orheterocyclyl group (more particularly a phenyl, naphthyl, furyl orthienyl group), which may be substituted, for example by one or moresubstituents selected from halogen (e.g. chlorine or bromine) atoms,straight- or branched-chain alkyl and alkoxy groups containing from 1 to6 carbon atoms, and trihalomethyl, e.g. trifluoromethyl groups], X informula I represents an ethylene or trans-vinylene group and Y informula I represents a carbonyl group or a group of formula III (whereinR⁶ and R⁷ are as hereinbefore defined), or else

(iii) R² represents a group R⁸ as hereinbefore defined, and X and Y informula I represent simultaneously ethylene and carbonyl, trans-vinyleneand carbonyl, or ethylene and --CH(OR⁷)-- groups respectively (R⁷ beingas hereinbefore defined).

As will be apparent to those skilled in the art, the structure shown ingeneral formula I has at least two centres of chirality, these twocentres of chirality being at the carbon atoms in positions 8 and 12respectively. In addition to these two centres of chirality, a furthercentre of chirality occurs when Y represents a group of formula III andstill further centres of chirality may occur in the group R². Thepresence of centres of chirality, as is well known, leads to theexistence of isomerism. However, the compounds of formula I of thepresent invention all have such a configuration that the side chainsattached to the ring carbon atoms in positions 8 and 12 are trans withrespect to each other. Accordingly, all isomers of general formula I,and mixtures thereof, which have those side chains, attached to the ringcarbon atoms in positions 8 and 12, in the trans-configuration arewithin the scope of the present invention. Preferably the groupsattached to the 8 and 12 positions of the cyclopentane ring are in thesame configuration as those in the natural products known asprostaglandins, viz. alpha and beta respectively.

In the present specification, unless otherwise indicated, alkyl groupsare straight- or branched-chain and contain from 1 to 6 carbon atoms.

The compounds of the invention possess valuable pharmacologicalproperties, for example, properties typical of the related series ofnatural products known as prostaglandins including, for example, theinhibition of gastric acid secretion, the production of hypotension,bronchodilatation, the stimulation of uterine contraction, theproduction of hypocholesteraemia and hypolipidaemia, and the stimulationof luteolysis.

For example, in laboratory screening tests the compounds produce 50% to100% inhibition of pentagastrin-induced gastric acid secretion in therat at doses between 1.0 and 100μg/kg animal body weight/minute whenadministered orally in solution in dilute aqueous alcohol [containingsodium chloride (about 0.9% w/v) and a small proportion of a wettingagent, e.g. Tween 80, to aid solubility; Tween 80 is a complex mixtureof polyoxyethylene ethers of mixed partial oleic esters of sorbitolanhydride]. More particularly, 50% inhibitions of pentagastrin-inducedgastric acid secretion were obtained in the rat at a dose of 4.0μg/kganimal body weight/minute of7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol and at adose of 6/0μg/kg animal body weight/minute of7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol.

In another laboratory test, the effects of aerosols containing compoundsof the invention were observed in conscious guinea pigs. Thus, guineapigs were continuously exposed to an aerosol containing a compound ofthe invention for a period of 3 minutes. After a pause of 30 seconds,the animals were exposed to an aerosol of the broncho-constrictorhistamine generated from a solution of histamine in water (2mg/ml) andthe time taken for convulsions to occur (termed the "preconvulsiontime") was noted. The concentration of compound of formula I in thesolution from which the aerosol was generated which would produce a 100%increase in preconvulsion time was then calculated mathematically fromresults obtained from solutions of compounds of formula I of variousconcentrations. For example, it was calculated that the preconvulsiontime obtained in animals pre-treated with an aerosol generated from anaqueous solution containing 142μg/ml of7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol, comparedwith the preconvulsion timed obtained in control animals pre-treatedwith a similar aerosol from which the compound of the invention wasabsent, would show an increase of 100% in the preconvulsion time.

In another laboratory test, rats were fed on a diet containing 0.5% w/wcholesterol and 0.25% w/w cholic acid for 7 days. During the last 3 dayssome of the rats received a daily oral dose of a solution of7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol in adilute (1% v/v) solution of alcohol in water at a rate of 100μg activecompound/kg animal body weight per day, while the other, control, ratsreceived only the aqueous alcohol vehicle. At the end of the 7th day thetreated animals had a 33% lower blood cholesterol level and a 43% lowerblood triglyceride level, compared with the control animals.

In yet another laboratory test,7-[2-(3-hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol producedluteolysis in more than 50% of pregnant hamsters when administeredsubcutaneously at a dose of 2mg/kg animal body weight in solution in adilute (1% v/v) solution of alcohol in water.

As well as the compounds specifically named in the above testdescriptions, other compounds of the invention showed useful levels ofactivity in these and other laboratory tests.

According to a feature of the present invention, compounds of generalformula I wherein R¹ represents a hydrogen atom, and R², X and Y are ashereinbefore defined, with the exception of those compounds wherein Yincludes a group --OR⁷ and R⁷ represents a carboxylic acyl group, areprepared by the process which comprises the acid hydrolysis of compoundsof the general formula: ##STR5## wherein R² and X are as hereinbeforedefined, Y¹ has the same significance as Y as hereinbefore defined withthe exclusion of groups of formula III or --CH(OR⁷)--, wherein R⁷ insaid formulae represents a carboxylic acyl group, the symbols R⁹represent identical alkyl groups or together form an ethylene linkageunsubstituted or substituted by identical alkyl groups on each carbonatom, the symbols R⁹ preferably representing together an unsubstitutedethylene linkage, and R¹⁰ represents a hydrogen atom, or when Y¹represents a group of formula III wherein R⁶ represents an alkyl groupand R⁷ represents a hydrogen atom, and group --OR¹⁰ optionallyrepresents a group, hereinafter represented as --OR¹¹, relatively inertto Grignard reagents but readily hydrolysed to a hydroxy group whenrequired, for example R¹¹ represents a trimethylsilyl group, and thehydroxy group forming part of the said group of formula III within thedefinition of Y¹ is then optionally in the form of a Grignardintermediate complex, that is to say the said hydroxy group is in a formwhich may be represented by the formula --OMgZ¹, wherein Z¹ represents ahalogen, e.g. bromine or iodine, atom.

The most suitable reaction conditions for the hydrolysis may readily bedetermined with a minimum of experimentation, and may vary according tothe values of the various symbols in formula V. When the symbol R¹⁰represents a group R¹¹, and especially when the hydroxy group formingpart of the group of formula III is in the form --OMgZ¹ the hydrolysisif preferably carried out stepwise, first hydrolysing --OMgZ¹ (whenpresent) to hydroxy, then hydrolysing --OR¹¹ to hydroxy, thenhydrolysing --C(OR⁹)₂ -- to keto, finally isolating the desired compoundof formula I. Optionally, but not necessarily, isolation of thehydrolysis product is carried out after each step of the stepwisehydrolysis.

The hydrolysis of --OMgZ¹ (when present) to hydroxy is preferablycarried out by means of aqueous ammonium chloride solution, preferablybelow room temperature, e.g. at about 0° C.

The hydrolysis of --OR¹¹ to hydroxy without simultaneous hydrolysis of--C(OR⁹)₂ -- to ketone is preferably carried out in a medium of aqueouslower alkanol, e.g. aqueous methanol, preferably in the presence of asmall amount of an organic acid, e.g. glacial acetic acid, at roomtemperature. On the other hand the hydrolysis of --OR¹¹ to hydroxy withthe sensibly simultaneous hydrolysis of --C(OR⁹)₂ -- to ketone may becarried out in the presence of a larger proportion of organic acid, e.g.acetic acid, and in the absence of alkanol, for example in a mixture ofglacial acetic acid and water (about 2:1 v/v), generally at around roomtemperature.

The hydrolysis of the group --C(OR⁹)₂ -- to ketone is generally carriedout by means of an organic acid in the presence of water, for exampleaqueous acetic acid, e.g. an aqueous acetic acid solution (e.g. 60-99%v/v), or p-toluenesulphonic acid in acetone containing a small amount ofwater, preferably at temperatures between 5° and 100° C, moreparticularly between 15° and 30° C, or alternatively by means of adilute inorganic acid, for example dilute hydrochloric acid, preferablyat temperatures between 0° and 100° C, more particularly between 45° and70° C. As a further alternative the hydrolysis may be effected bysubjecting the compound to chromatography, preferably using an eluantcontaining some organic acid, for example glacial acetic acid. By thismeans purification is effected simultaneously with hydrolysis.

Compounds of formula I wherein R¹ represents a carboxylic acyl group,and those wherein the symbol Y represents a group containing the symbolR⁷ and wherein R⁷ represents a carboxylic acyl group, and R² and X areas hereinbefore defined, are prepared, according to another feature ofthe invention, by the acylation of corresponding alcohols of formula Iby the application or adaptation of known methods, for example byreaction with the appropriate acid anhydride [for example aceticanhydride when R¹ and, where applicable, R⁷ in the desired productrepresent acetyl group(s)] in the presence of a base, e.g. pyridine,preferably at ambient temperature, optionally in the presence of aninert organic solvent such as an aromatic hydrocarbon (e.g. benzene). Itis generally easier to acylate the heptanol chain then it is to acylatethe hydroxy group (when present) within the group Y, especially when Yrepresents a group of formula III wherein R⁶ represents an alkyl group.Accordingly, when it is desired to acylate a hydroxy group within thegroup Y as well as to acylate the heptanol chain, more vigorousconditions such as use of a stronger base, or a higher temperature, orthe absence of inert organic solvent, or else longer reaction times, aregenerally selected.

Compounds of formula V wherein X represents a trans-vinylene group, Y¹represents a carbonyl group and R¹⁰ represents a hydrogen atom, R² andR⁹ being as hereinbefore defined, may be prepared by the reaction ofcompounds of the general formula: ##STR6## (wherein R⁹ is ashereinbefore defined), either with compounds of the general formula:

    (R.sup.12).sub.3 P═CHCOR.sup.2                         VII

(wherein R² is as hereinbefore defined and R¹² represents an alkyl groupor a phenyl group unsubstituted or substituted by an alkyl group, andadvantageously represents a phenyl or n-butyl group), preferably in thepresence of an inert organic solvent and preferably at a temperaturebetween 20° and 100° C, for example in the presence of tetrahydrofuranas solvent at the reflux temperature of the reaction mixture or in thepresence of hexamethylphosphotriamide as solvent at between 95° and 100°C. or, preferably, with compounds of the general formula:

    (R.sup.13 O).sub.2 P(O)CH.sub.2 COR.sup.2                  VIII

(wherein R² is as hereinbefore defined and R¹³ represents an alkyl groupof from 1 to 4 carbon atoms, preferably a methyl group) in the presenceof a strong base, for example sodium hydride, and preferably in thepresence of an inert organic solvent, for example an ether (e.g.tetrahydrofuran), and preferably at or near room temperature.

Compounds of formula V wherein either X represents an ethylene group orY¹ represents a hydroxymethylene group, or wherein both X and Y¹respectively have those meanings, R², R⁹ and R¹⁰ being as hereinbeforedefined (hereinafter referred to as "compounds of formula Va"), may beprepared by the reduction of compounds of formula V wherein either Xrepresents a trans-vinylene group or Y¹ represents a carbonyl group, orwherein both X and Y¹ respectively have those meanings, R², R⁹ and R¹⁰being as hereinbefore defined (hereinafter referred to as "compounds offormula Vb"). Thus:

(a) Compounds of formula Va wherein X represents an ethylene ortrans-vinylene group and Y¹ represents a hydroxymethylene group may beprepared by reduction of the corresponding compounds of formula Vbwherein X represents an ethylene or trans-vinylene group and Y¹represents a carbonyl group, using means and conditions capable ofreducing carbonyl groups to hydroxymethylene groups without affectingcarbon-carbon double bonds. The reduction is preferably effected by ametal borohydride (e.g. sodium borohydride or potassium borohydride),usually in an aqueous, alcoholic or aqueous alcoholic medium and atbetween -40° and +30° C, preferably between -5° and +15° C, optionallyin the presence of a base, for example an alkali metal hydroxide (e.g.aqueous sodium hydroxide or aqueous potassium hydroxide) or, especiallywhen potassium borohydride is employed, in aqueous or aqueous alcoholicconditions buffered at a pH of from pH 7 to pH 9, e.g. at pH 8 (e.g. bythe addition of aqueous citric acid solution). Alternatively thereduction is carried out by reaction with aluminium isopropoxide, in thepresence of isopropanol, preferably as the solvent medium, at anelevated temperature, advantageously at the reflux temperature of thereaction mixture.

(b) Compounds of formula Va wherein X represents an ethylene group andY¹ represents a carbonyl or hydroxymethylene group may be prepared byreduction of the corresponding compounds of formula Vb wherein Xrepresents a trans-vinylene group and Y¹ represents a carbonyl orhydroxymethylene group, with means and in conditions capable of reducingcarbon-carbon double bonds without affecting carbonyl groups. Thereduction is preferably effected by hydrogenation in the presence of ahydrogenation catalyst, for example palladium on charcoal or rhodium oncharcoal, in the presence of an inert organic solvent, for example alower alkanol, e.g. ethanol, generally at ambient temperature andelevated pressure, e.g. at a hydrogen pressure of 15 kilograms persquare centimeter.

(c) Compounds of formula Va wherein X represents an ethylene group andY¹ represents a hydroxymethylene group may be prepared by reduction ofcorresponding compounds of formula Vb with means and in conditionscapable of reducing any carbonyl groups present to hydroxymethylenegroups and any trans-vinylene groups present to ethylene groups. Thereduction is preferably effected by hydrogenation in the presence of ahydrogenation catalyst, for example palladium on charcoal or Raneynickel, in the presence of an inert organic solvent, for example a loweralkanol, e.g. ethanol, preferably at an elevated pressure, e.g. at ahydrogen pressure of 15 kilograms per square centimeter.

Compounds of formula V wherein X represents a trans-vinylene group, Y¹represents a group of formula III wherein R⁶ represents an alkyl groupcontaining from 1 to 4 carbon atoms and R⁷ represents a hydrogen atom,R², R⁹ and R¹⁰ being as hereinbefore defined, may be prepared, by meansof the Grignard reaction followed by hydrolysis, from compounds of thegeneral formula IX or X: ##STR7## wherein R², R⁹ and R¹¹ are ashereinbefore defined, and R⁶ ' represents a straight- or branched-chainalkyl group containing from 1 to 4 carbon atoms, preferably methyl. TheGrignard reagent used may be represented by the general formula XI orXII respectively: ##STR8## wherein R², R⁶ ' and Z¹ are as hereinbeforedefined.

The Grignard reaction is carried out in conditions typical of Grignardreactions, for example in an ether (e.g. diethyl ether) at or near roomtemperature, to form an intermediate of the general formula: ##STR9##(wherein R², R⁶ ', R⁹, R¹¹ and Z¹ are as hereinbefore defined) withingeneral formula V.

As is hereinbefore described, the intermediate compound of formula XIII,generally without isolation, is then converted by hydrolysis to acompound of the general formula: ##STR10## (wherein R², R⁶ ', R⁹ and R¹¹are as hereinbefore defined) within general formula V which is thenhydrolysed to the corresponding compound of formula V wherein R¹⁰represents a hydrogen atom, X represents a trans-vinylene group, Y¹represents a group of formula III wherein R⁶ represents an alkyl groupand R⁷ represents a hydrogen atom, and R² and R⁹ are as hereinbeforedefined, as is hereinbefore described.

The compounds of formulae IX and X may be prepared from the appropriatealcohols of formula V wherein R¹⁰ represents a hydrogen atom, Xrepresents a trans-vinylene group, Y¹ represents a carbonyl group, andR² and R⁹ are as hereinbefore defined, by the application or adaptationof known methods for the introduction of the R¹¹ group. When R¹¹represents a trimethylsilyl group, it may be introduced by reaction ofthe alcohol with hexamethyldisilazane, in the presence oftrimethylchlorosilane or hydrogen chloride gas, in dry conditions, forexample in dry tetrahydrofuran as solvent.

Compounds of formula V wherein X represents an ethylene group, Y¹represents a group of formula III wherein R⁶ represents an alkyl groupand R⁷ represents a hydrogen atom, and R², R⁹ and R¹⁰ are ashereinbefore defined, may be prepared by the reduction of correspondingcompounds of formula V wherein X represents a trans-vinylene group bythe application of methods hereinbefore described for the reduction ofcarbon-carbon double bonds in compounds of formula Vb to form compoundsof formula Va wherein X represents an ethylene group.

The compounds of formula VI may be prepared by the reaction sequencewhich may be illustrated schematically as follows: ##STR11## wherein R⁹is as hereinbefore defined and R¹⁴ represents a hydrogen atom or asuitable acid labile group. Suitable acid labile groups represented byR¹⁴ are those which are easily removed by acid hydrolysis and do notcause side reactions, e.g. the 2-tetrahydropyranyl group unsubstitutedor substituted by, for example, at least one lower alkyl group.

The reaction of an aldehyde of formula XV and an enamine (e.g. themorpholine enamine) of cyclopentanone to yield an alcohol of formula XVIis carried out in an inert organic solvent, for example an aromatichydrocarbon (e.g. benzene) with continuous removal of water, preferablyat 60°-120° C., followed by hyrolysis in aqueous acid conditions (e.g.with hydrochloric acid), preferably at ambient temperature, and thenheating with an acid (e.g. concentrated hydrochloric acid), preferablyat about 100° C., and preferably in an inert organic solvent such as analcohol (e.g. butanol) to cause the double bond to migrate from theexocyclic to the endocyclic position.

The alcohols of general formula XVI are reacted with a source ofhydrogen cyanide (e.g. acetone cyanohydrin) preferably in the presenceof a base, for example an alkali metal carbonate (e.g. sodiumcarbonate), in an aqueous organic solvent, for example an aqueous loweralkanol (e.g. aqueous methanol), preferably at 50°-110° C. andadvantageously at the reflux temperature of the solvent employed, togive ketonitriles of formula XVII.

The ketals of general formula XVIII are prepared from the ketonitrilesof formula XVII by the application or adaptation of known methods forthe preparation of ketals from ketones, for example by the reaction of acompound of formula XVII with the appropriate alcohol or diol in thepresence of an acidic catalyst, for example p-toluenesulphonic acid,with continuous removal of water. Advantageously the reaction iseffected in the presence of an inert organic solvent, for example anaromatic hydrocarbon (e.g. benzene), at an elevated temperature, withthe continuous removal of water by means of a Dean and Stark apparatus.

The ketals of general formula XVIII are reduced in an inert organicsolvent, for example a lower dialkyl ether (e.g. diethyl ether),preferably at a temperature between -80° C. and +30° C., to compounds offormula VI by means of known complex metal reducing agents, preferably adialkylaluminium hydride (e.g. diisobutylaluminium hydride) in an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene).

The enamines of cyclopentanone used as initial starting materials in theprocess of preparation of the compounds of formula VI may be preparedfrom cyclopentanone and secondary amines, preferably in an aromatichydrocarbon solvent (e.g. benzene or toluene), by the method of G. Storket al, J. Am. Chem. Soc., 1963, 85, 207. Preferred secondary amines are5- or 6-membered nitrogen-containing secondary heterocyclic bases, whichmay carry in the ring one or two additional hetero atoms selected fromoxygen and nitrogen (e.g. morpholine). When the amine contains more thanone nitrogen atom, one of the nitrogen atoms is secondary and theremainder are tertiary.

By the term "known methods" as used in this specification is meantmethods heretofore used or described in the literature.

As will be readily appreciated by those skilled in the art, the isomericforms of the compounds of the invention arising from the aforementionedcentres of chirality may be separated by the application or adaptationof known methods, for example diastereoisomeric forms may be separatedby chromatography using selective adsorption from solution or from thevapour phase onto suitable adsorbents, or by fractional crystallisationfrom suitable solvent systems.

Preferred compounds of the present invention are the compounds withinformula I as hereinbefore defined and wherein one or more of thefollowing conditions applies:

(a) Y represents a group of formula III wherein R⁶ represents a methylgroup;

(b) R² represents a group of formula II wherein R⁴ represents a methylgroup;

(c) R² represents a phenoxymethyl group.

Compounds of particular importance are the following:

7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol,

7-[2-(3-hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol,

7-[2-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol,

7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol and

7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol.

The following Examples illustrate the compounds of the present inventionand their preparation.

EXAMPLE 1 7-[2-(4-Methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol (i)Preparation of 2-(7-hydroxyheptyl)cyclopent-2-en-1-one

A mixture of 7-(2-tetrahydropyranyloxy)heptanal (22 g.) and1-morpholinocyclopentene, i.e. the morpholine enamine of cyclopentanone,(21.4 g.) in benzene (25 ml.) was heated under reflux for 12 hours undernitrogen, and the water liberated was continuously removed with a Deanand Stark head. Benzene (10 ml.) and then, dropwise, 18% hydrochloricacid (28 ml.) were added and the mixture was stirred for 2 hours. Theorganic layer was separated and evaporated. Concentrated hydrochloricacid (72 ml.) and butanol (300 ml.) were added to the residue. Themixture was heated at 100° C. for 1 hour, and then the solution wasconcentrated to give an oil. Diethyl ether was added, and the ethersolution was washed with aqueous sodium bicarbonate and then water, anddried over sodium sulphate. The solvent was evaporated and the residuewas distilled under reduced pressure to give2-(7-hydroxyheptyl)cyclopent-2-en-1-one (11.7 g.), b.p. 125°-170° C/0.15mm.Hg, n_(D) ²⁵ 1.490, μ_(max) 228mμ (ethanol).

The 7-(2-tetrahydropyranyloxy)heptanal used as starting material in theabove procedure was prepared as follows:

3,4-Dihydro-2H-pyran (272 g.) was added dropwise at 40° C. with stirringto a mixture of 7-hydroxyheptanenitrile (284 g.) and concentratedhydrochloric acid (10 drops). The temperature was allowed to rise to 65°C. and was maintained at this level for one hour. The solution wascooled and benzene (500 ml.) was added. The solution was washed withaqueous sodium bicarbonate and then water, and dried over sodiumsulphate. The solvent was removed in vacuo, and the residue distilledunder reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanenitrile(411 g.), b.p. 100°-130° C./0.1 mm.Hg, n_(D) ²⁵ 1.455.

Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was addeddropwise at 10° C. to a stirred solution of7-(2-tetrahydropyranyloxy)heptanenitrile (20.6 g.) in dry diethyl ether(200 ml.). The solution was stirred at 10° C. for 30 minutes and wasthen added to 2N aqueous sulphuric acid (300 ml.) at 0° C. The mixturewas heated at 30° C. for 30 minutes, and then saturated with sodiumchloride and the layers were separated. The aqueous layer was extractedwith diethyl ether and the combined organic layers were washed withaqueous sodium bicarbonate, and then aqueous sodium chloride, and driedover sodium sulphate. The solvent was evaporated and the residue wasdistilled under reduced pressure to give7-(2-tetrahydropyranyloxy)heptanal (12.7 g.), b.p. 78°-106° C./0.1mm.Hg, n_(D) ²⁵ 1.456.

The above procedure may also be carried out replacing the7-(2-tetrahydropyranyloxy)heptanal by 7-hydroxyheptanal [prepared asdescribed above for 7-(2-tetrahydropyranyloxy)heptanal, but using7-hydroxyheptanenitrile in place of7-(2-tetrahydropyranyloxy)heptanenitrile].

Advantageously 7-hydroxyheptanal can be prepared in one step fromaleuritic acid using the method described below.

Sodium hydroxide (13.2 g.) in water (660 ml.) was added to aleuriticacid (100 g.)and the suspension stirred at 0° to 10° C. To the resultingsuspension of sodium aleuritate was added sodium periodate (80 g.) inwater (800 ml.) over 1 hour, without allowing the temperature to riseabove 15° C. Dichloromethane (200 ml.) was then added and the mixturestirred for a further 2.5 hours at 15° C. A further amount ofdichloromethane (300 ml.) and saturated aqueous sodium bicarbonate (100ml.) were added and the mixture vigorously stirred. The precipitatedsodium iodate was removed by filtration and the dichloromethane layerseparated. The aqueous phase was washed with dichloromethane (500 ml.)and the combined dichloromethane extracts dried over anhydrous magnesiumsulphate. Removal of the dichloromethane in vacuo below 40° C. gave7-hydroxyheptanal (43 g.), ν_(max) 3400 cm⁻¹, 2700 cm⁻¹, 1710 cm⁻¹.

(ii) Preparation of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile

A mixture of 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (17 g.), acetonecyanohydrin (8.5 g.), 6% aqueous sodium carbonate (8 ml.) and methanol(50 ml.) was stirred and heated under reflux for 4 hours. Methanol wasremoved in vacuo, water (100 ml.) was added and the mixture wasextracted with diethyl ether and dried over magnesium sulphate. Thesolvent was removed by evaporation, and the residue was distilled underreduced pressure to give2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g.), b.p.144°-182° C./0.15 mm.Hg, n_(D) ²⁵ 1.4795.

(iii) Preparation of7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane

A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.),ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene(160 ml.) was heated to reflux for 31/2 hours with continuous removal ofwater. The mixture was cooled to ambient temperature, anhydrous sodiumcarbonate was added, and after filtration through a bed of sodiumcarbonate, the solvent was removed under reduced pressure. The residuewas distilled under reduced pressure to give7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p.166°-182° C./0.1 mm.Hg. This material was used as a starting material inthe next stage, an aliquot being redistilled to b.p. 177°-179° C./0.1mm.Hg for elemental analysis:

Found: C, 67.1; H, 9.2; N, 4.89%; C₁₅ H₂₅ NO₃ requires: C, 67.37; H,9.42; N, 5.24%.

(iv) Preparation of7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane

A solution of diisobutylaluminium hydride (53 g.) in dry benzene (145ml.) was added, with rapid stirring, to a solution of7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (43.2 g.) in drydiethyl ether (432 ml.) at 10°-15° C. Stirring at ambient temperaturewas continued for 11/2 hours and the mixture was added to 2N aqueousacetic acid (1 liter) at a temperature lower than 15° C. The organicphase was separated and the aqueous layer was extracted with diethylether. The combined organic phases were washed with aqueous sodiumbicarbonate, dried over sodium sulphate, the solvents removed in vacuoand the residue distilled under reduced pressure to give7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (25.3 g.), b.p.164°-200° C./0.04-0.05 mm.Hg, ν_(max). 1710 cm⁻¹, 2700 cm⁻¹ (liquidfilm).

(v) Preparation of6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane

A mixture of 7-formyl-6-(7-hydroxypheptyl)-1,4-dioxaspiro[4,4]nonane(3.88 g.) and 2-methylhexanoylmethylenetriphenylphosphoran (6.0 g.) indry tetrahydrofuran (30 ml.) was heated to reflux under nitrogen for 18hours. The solvent was removed in vacuo and the residue triturated withpetroleum ether (b.p. 60°-80° C.), allowed to stand at 0° C., filteredto remove triphenylphosphine oxide and the filtrate evaporated to give6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane(5.56 g.), ν_(max) 1620 cm⁻¹, 1660 cm⁻¹.

2-Methylhexanoylmethylenetriphenylphosphorane, used as a startingmaterial, was prepared as follows:

A solution of 1-chloro-3-methylheptan-2-one (49.4 g.) andtriphenylphosphine (79.5 g.) in chloroform (250 ml.) was saturated withnitrogen and refluxed under nitrogen overnight. The chloroform wasremoved in vacuo and the residue (crude3-methyl-2-oxoheptyltriphenylphosphonium chloride) was added portionwiseto a solution of sodium carbonate (109 g.) in water (1500 ml.) and themixture was stirred vigorously for 24 hours. The solution was extractedwith diethyl ether, and the ethereal extracts were dried over magnesiumsulphate. The solvent was removed by evaporation and the residue wascooled and triturated with petroleum ether (b.p. 60°-80° C.) to give2-methylhexanoylmethylenetriphenylphosphorane (35.2 g.), m.p. 107°-109°C.

1-Chloro-3-methylheptan-2-one, used as starting material, was preparedas follows:

2-Methylhexanoyl chloride (42.5 g.) was added dropwise at -40° C. to asolution of diazomethane (24 g.) in diethyl ether (600 ml.) and thesolution was stirred for 1 hour at ambient temperature. Hydrogenchloride gas was then bubbled into the solution until it was fullysaturated. Crushed ice was added to give approximately 1 liter ofaqueous solution. The organic layer was separated and the aqueous layerwas extracted with diethyl ether. The combined organic layers were driedover magnesium sulphate, evaporated, and the residue distilled underreduced pressure to give 1-chloro-3-methyl-heptan-2-one (49.5 g.), b.p.100°-110° C./13 mm.Hg.

As an alternative method for the preparation of6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane,the following procedure was followed:

Dimethyl 3-methyl-2-oxoheptylphosphonate (5.1 g.; prepared as describedin the Specification of Netherlands Patent Application No. 7203126) indry tetrahydrofuran (20 ml.) was added dropwise to a stirred suspensionof sodium hydride (0.52 g.) in dry tetrahydrofuran (150 ml.) at ambienttemperature under nitrogen. The reaction mixture was stirred at ambienttemperature until hydrogen evolution had ceased, and then treated with asolution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (5.1g.) in dry tetrahydrofuran (50 ml.). After stirring for a further periodof 2 hours at ambient temperature the reaction mixture was acidified topH 4 with glacial acetic acid and then concentrated under reducedpressure. The residue was triturated with diethyl ether and filtered.The filtrate was washed with dilute aqueous sodium carbonate solutionand water respectively, then dried over sodium sulphate. Removal of thesolvent under reduced pressure gave crude6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane(7.6 g.), ν_(max) (liquid film) 3450 cm⁻¹, 1680 cm⁻¹, 1660 cm⁻¹, 1620cm⁻¹, 1380 cm⁻¹, 1040 cm⁻¹, which was used in the next stage withoutfurther purification being necessary.

(vi) Preparation of7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol

A mixture of6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane(1.0 g.) and hydrochloric acid (25 ml; 1N) was stirred at 60° C. for 2hours, cooled to ambient temperature and extracted with diethyl ether.The ether extract was washed with 2N aqueous sodium carbonate solutionand water respectively then dried over magnesium sulphate. Removal ofthe solvent under reduced pressure gave a crude product (0.7 g.) whichwas purified by preparative thin layer chromatography on silica gel,using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v)as eluant, to give7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol (0.38 g.),ν_(max) (liquid film) 3450 cm⁻¹, 1730 cm⁻¹, 1690 cm⁻¹, 1660 cm⁻¹, 1380cm⁻¹, 995 cm⁻¹ ; λ_(max). (ethanol) 230 nm (ε = 13,600); Elementalanalysis: Found: C, 74.9; H, 11.0%; C₂₁ H₃₆ O₃ requires C, 74.95; H,10.8%; N.M.R. (approximately 10% solution in deuterochloroform):Triplets at 3.57 δ (J = 6 cycles/sec.) and 0.88 δ, doublet of doubletsat 6.81 δ (J = 15.5 cycles/sec. and J = 7 cycles/sec.), doublets at 6.20δ (J = 15.5 cycles/sec.) and 1.11 δ (J = 7 cycles/sec.), broad singlet2.0 δ.

EXAMPLE 2 7-[2-(3-Hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane

6-(7-Hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane[1.0 g.; prepared as hereinbefore described in Example 1 (v)] wasdissolved in methanol (50 ml.) and added to aqueous sodium citratesolution (130 ml.; 2% w/v. To this stirred solution, at -5° to 0° C,solid potassium borohydride (2.24 g.) was added portionwise at such arate as to avoid undue effervescence and the reaction mixture wasmaintained at pH 8 by the occasional addition of aqueous citric acidsolution (10% w/v). After the final addition of the potassiumborohydride the reaction mixture was stirred at -5° to 0° C. and pH 8for 90 minutes. Acetone (50 ml.) was then added, the solution wassaturated with sodium chloride, and extracted with diethyl ether. Thecombined ether extracts were washed with a saturated solution of sodiumchloride in hydrochloric acid (2N) and saturated sodium chloridesolution respectively, then dried over sodium sulphate. Removal of thesolvent under reduced pressure gave crude6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane(0.6 g.), ν_(max) 3400 cm⁻¹, 1040 cm⁻¹, 970 cm⁻¹, which was used in thenext stage without further purification.

(ii) Preparation of7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol.

A mixture of crude6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane(0.5 g.) and hydrochloric acid (50 ml; 2N) was stirred at 60° C. for 2hours, cooled to ambient temperature and then extracted with diethylether. The ether extract was washed with water and dried over magnesiumsulphate. Removal of the solvent under reduced pressure gave a crudeproduct (0.4 g.) which was purified by preparative thin layerchromatography on silica gel, using a mixture of diethyl ether, ethylacetate and hexane (2:1:1 v/v) as eluant, to give7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.15 g.),ν_(max) 3400 cm⁻¹, 1725 cm⁻¹, 970 cm⁻¹ ; Elemental analysis: Found C,74.8; H, 11.7%; C₂₁ H₃₈ O₃ requires C, 74.5; H, 11.53%; N.M.R.(approximately 10% solution in deuterochloroform): multiplets at 5.7-5.5δ, 3.98 δ and 1.05-0.7 δ, triplet at 3.6 δ (J = 6 cycles/sec.), basedsinglet at 2.05 δ.

EXAMPLE 3 7-[2-(3-Hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane

A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [6g; prepared as hereinbefore described in Example 1(iv)] andhexanoylmethylenetriphenylphosphorane (8.5 g.) in dry tetrahydrofuran(50 ml.) was heated to reflux under nitrogen for 16 hours. The solventwas removed in vacuo and the residue triturated with petroleum ether(b.p. 60°-80° C.), cooled to 0° C. for 1 day, filtered to removetriphenylphosphine oxide and the filtrate evaporated. The residue wasagain triturated with petroleum ether (b.p. 60°-80° C.) to removefurther triphenylphosphine oxide, filtered, and evaporated to give6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (7.5g.), ν_(max) 1620 cm⁻¹, 1660 cm⁻¹.

Hexanoylmethylenetriphenylphosphorane, used as starting material, wasprepared as follows:

A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60g.) in chloroform (50 ml.) was saturated with nitrogen and refluxedunder nitrogen overnight. The chloroform was removed in vacuo and theresidue was dissolved in dichloromethane (150 ml.). Dry diethyl ether(600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphoniumchloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was addedportionwise to a solution of sodium carbonate (25 g.) in water (250 ml.)and the mixture was stirred vigorously for 24 hours. The solution wasextracted with diethyl ether, and the ethereal extracts were dried overmagnesium sulphate. The solvent was removed by evaporation and theresidue was cooled and triturated with petroleum ether (b.p. 40°-60° C).The solid thus obtained was recrystallised from petroleum ether (b.p.60°-80° C.) to give hexanoylmethylenetriphenylphosphorane (17 g.), m.p.73°-74° C.

(ii) Preparation of6-(7-trimethylsilyloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane.

Hexamethyldisilazane (7.5 ml.) and trimethylchlorosilane (1.5 ml.) wereadded to a stirred solution of6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (2.0g.) in dry tetrahydrofuran (100 ml.) and the mixture was stirred at roomtemperature for 24 hours. The mixture was then filtered and the solventwas removed from the filtrate in vacuo. Xylene (20 ml.) was added to theresidue and the solvent was again removed in vacuo. This process ofadding xylene and then removing solvent in vacuo was repeated twicemore, and the petroleum ether (b.p. 60°-80° C.) was added to theresidue. The mixture was filtered, and the filtrate concentrated invacuo to give6-(7-trimethylsilyloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane(2.1 g.), ν_(max) 845 cm⁻¹, 1250 cm⁻¹.

(iii) Preparation of7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsilyloxyheptyl)-1,4-dioxaspiro[4,4]nonane

A solution (2.86 ml.) of methyl magnesium iodide in diethyl ether[prepared, in the manner well known in the art, from methyl iodide (6g.), magnesium (1.07 g.) and diethyl ether (20 ml.)] was added dropwiseto a stirred solution of6-(7-trimethylsilyloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane(2.1 g.) in diethyl ether (80 ml.) at room temperature. The mixture wasstirred for 30 minutes and a further quantity (1.09 ml. ) of thesolution of methyl magnesium iodide in diethyl ether was then addeddropwise. The mixture was stirred for a further 30 minutes and thenadded to saturated aqueous ammonium chloride solution (250 ml.) at 0° C.and stirred for 15 minutes. The ether layer was separated and theaqueous layer extracted with diethyl ether. The combined ether layerswere concentrated in vacuo to give crude7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsilyloxyheptyl)-1,4-dioxaspiro[4,4]nonane(1.9 g.), ν _(max) 845 cm⁻¹, 1250 cm⁻¹, 3400 cm⁻¹, pure enough to use inthe next stage.

(iv) Preparation of6-(7-hydroxyheptyl)-7-(3-hydroxy-3-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane

Methanol (30 ml.), water (15 ml.) and glacial acetic acid (3 drops) wereadded to7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsilyloxyheptyl)-1,4-dioxaspiro[4,4]nonane(0.5 g.) and the mixture was stirred at room temperature for 30 minutes.An excess of diethyl ether was then added and the resulting solution waswashed with dilute aqueous sodium bicarbonate solution and sodiumchloride solution respectively, and dried over sodium sulphate, to givecrude6-(7-hydroxyheptyl)-7-(3-hydroxy-3-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane(0.33 g.), ν_(max) 3400 cm⁻¹, pure enough to use in the next stage.

(v) Preparation of7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol

6-(7-Hydroxyheptyl)-7-(3-hydroxy-3-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane(0.33 g.) was hydrolysed by subjecting it to preparative thin layerchromatography on silica gel, eluting with a mixture of hexane, dichloromethane, tetrahydrofuran and glacial acetic acid (30:10:3:3 v/v), togive 7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.12g.), ν_(max) 975 cm⁻¹, 1720 cm⁻¹, 3400 cm⁻¹, N.M.R. (approximately 10%solution in deuterochloroform): triplet at 0.9 δ, singlet at 1.30 δ,multiplets at 1.05-2.5 δ, singlet at 1.5 δ, triplet at 3.62 δ(J = 6cycles/second), multiplet at 5.5-5.7 δ.

Elemental analysis: Found: C, 74.9; H, 11.3%; C₂₁ H₃₈ O₃ requires: C,74.5; H, 11.3%.

EXAMPLE 4 7-[2-(3-Cyclohexyl-3-oxopropyl)-5-oxocyclopentyl]heptanol (i)Preparation of7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane

A solution of dimethyl 2-cyclohexyl-2-oxoethylphosphonate (10.1 g.) indry tetrahydrofuran (40 ml.) was added to a stirred suspension of sodiumhydride (1.04 g.) in dry tetrahydrofuran (300 ml.). The mixture wasstirred at room temperature until the evolution of hydrogen had ceased,then treated dropwise with a solution of7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [10.2 g; preparedas described in Example 1(iv) above] in dry tetrahydrofuran (100 ml.)and stirred for a further 2 hours. The mixture was acidified to pH 4 bythe addition of glacial acetic acid, the solvents were removed in vacuo,the residue was triturated with diethyl ether and the solid filteredoff. The ethereal solution was washed with aqueous sodium carbonatesolution, dried over magnesium sulphate, and evaporated to dryness, togive7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane(16 g.), ν_(max) 3400 cm⁻¹, 1680 cm⁻¹, 1650 cm⁻¹, 1620 cm⁻¹, 1040 cm⁻¹.

The dimethyl 2-cyclohexyl-2-oxoethylphosphonate, used as startingmaterial in the above preparation was prepared by treating a stirredsolution of dimethyl methylphosphonate (108 g.) in dry tetrahydrofuran(780 ml.) at -45° to -60° C, under nitrogen, dropwise, during 20minutes, with a solution of butyl lithium (64 g.) in n-hexane (400 ml.).Stirring was continued at that temperature for a further 10 minutes, andthen the mixture was cooled to -60° C. and treated, dropwise during 10minutes, with a solution of ethyl cyclohexanecarboxylate (68.2 g.) indry tetrahydrofuran (200 ml.). The mixture was stirred at -60° C. for afurther 90 minutes and then at room temperature for 3 hours, and then itwas treated with glacial acetic acid (84 ml.), evaporated to dryness invacuo and the residue treated with water. The mixture was extractedtwice with diethyl ether and the combined ethereal extracts were washedwith water, dried over sodium sulphate and evaporated to dryness invacuo. The residue was distilled to give dimethyl2-cyclohexyl-2-oxoethylphosphonate (52 g.), b.p. 125°-130° C./0.005mm.Hg, ν_(max) 1700 cm⁻¹, 1260 cm⁻¹, 1040 cm⁻¹.

(ii) Preparation of7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane

A solution of7-(3-cyclohexyl-3-oxoprop-1-enyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane(2.0 g.) in ethanol (50 ml.) was catalytically reduced with hydrogen ata pressure of 7 kg/cm² and in the presence of a 5% palladium on charcoalcatalyst (0.5 g.) at room temperature for 3 hours. The catalyst was thenfiltered off and the ethanol evaporated off from the filtrate, to give7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane(1.4 g.), ν_(max) 3450 cm⁻¹, 1700 cm⁻¹, 1040 cm⁻¹.

(iii) Preparation of7-[2-(3-cyclohexyl-3-oxopropyl)-5-oxocyclopentyl]heptanol

A mixture of7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane(0.5 g.) in hydrochloric acid (20 ml; 1N) was stirred at 60° C. for 2hours, cooled to ambient temperature and extracted with diethyl ether.The ethereal extract was washed with water, then dried over sodiumsulphate. Removal of the solvent under reduced pressure gave a crudeproduct (0.4 g.) which was purified by preparative thin layerchromatography on silica gel, using a mixture of diethyl ether, ethylacetate and hexane (2:1:1 v/v) as eluant, to give7-[2-(3-cyclohexyl-3-oxopropyl)-5-oxocyclopentyl]heptan-1-ol (0.16 g.),ν_(max) 3450 cm⁻¹, 1730 cm⁻¹, 1700 cm⁻¹, 1060 cm⁻¹ ; Elemental analysis:Found: C, 74.6; H, 10.7%; C₂₁ H₃₆ O₃ requires C, 74.95; H, 10.78%.

EXAMPLE 5 7-[2-(3-Hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol

7-(3-Hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane[0.5 g; prepared as hereinbefore described in Example 3(iii)], water (10ml.) and glacial acetic acid (20 ml.) were left to stand together atroom temperature for 6 hours. The solution was then evaporated in vacuoat a temperature below 50° C. Ethyl acetate (150 ml.) was added to theresidue and the resulting solution was washed with water until the pH ofthe washings was 5, dried over sodium sulphate, and evaporated to give acrude product (0.37 g.). The crude product was subjected to preparativethin layer chromatography on silica gel, using a mixture of toluene,dioxan and acetic acid (65:15:1 by volume) as eluant, eluting twice, togive 7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.12g.).

Elemental analysis: Found: C, 72.9; H, 11.2%; C₂₁ H₃₈ O₃ :1/2H₂ Orequires C, 72.6; H, 11.3%

EXAMPLE 6 7-[2-(3-Hydroxy-3-methylhex-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-hydroxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that described in Example 3(i) forthe preparation of6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane, butsubstituting the appropriate quantity ofbutyrylmethylenetriphenylphosphorane for thehexanoylmethylenetriphenylphosphorane used as a starting material, therewas prepared6-(7-hydroxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 1620 cm⁻¹, 1660 cm⁻¹.

The butyrylmethylenetriphenylphosphorane (m.p. 158°-161° C.), used as astarting material in the above preparation, was prepared from1-chloropentan-2-one, via 2-oxopentyltriphenylphosphonium chloride (m.p.159° C.), by proceeding in a similar manner to that hereinbeforedescribed in Example 3(i) for the preparation ofhexanoylmethylenetriphenylphosphorane from 1-chloroheptan-2-one.

(ii) Preparation of6-(7-trimethylsiloxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(ii) for the preparation of6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane,but substituting the appropriate quantity of6-(7-hydroxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane forthe 6-(7-hydroxy-heptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared6-(7-trimethylsiloxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 845 cm⁻¹, 1250 cm⁻¹.

(iii) Preparation of7-(3-hydroxy-3-methylhex-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(iii) for the preparation of7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane,but substituting the appropriate quantity of6-(7-trimethylsiloxyheptyl)-7-(3-oxohex-1-enyl)-1,4-dioxaspiro[4,4]nonanefor the6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared7-(3-hydroxy-3-methylhex-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 845 cm⁻¹, 1250 cm⁻¹, 3400 cm⁻¹.

(iv) Preparation of7-[2-(3-hydroxy-3-methylhex-1-enyl)-5-oxocyclopentyl]heptanol

By proceeding in a similar manner to that hereinbefore described inExample 5 for the preparation of7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol, butsubstituting the appropriate quantity of7-(3-hydroxy-3-methylhex-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonanefor the7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared7-[2-(3-hydroxy-3-methylhex-1-enyl)-5-oxocyclopentyl]heptanol. Elementalanalysis: Found: C, 73.3; H, 10.9%; C₁₉ H₃₄ O₃ requires C, 73.5; H,11.0%. N.M.R. (approximately 10% w/v solution in deuterochloroform):triplet at 0.9δ, singlet at 1.3δ, multiplets at 1.05-2.5δ, singlet at1.75δ, triplet at 3.62δ, multiplet at 5.5-5.7δ.

EXAMPLE 77-[2-(5-Ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-hydroxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(i) for the preparation of6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane, butsubstituting the appropriate quantity of3-ethoxypropionylmethylenetriphenylphosphorane for thehexanoylmethylenetriphenylphosphorane used as a starting material, therewas prepared6-(7-hydroxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 1620 cm⁻¹, 1660 cm⁻¹.

The 3-ethoxypropionylmethylenetriphenylphosphorane (m.p. 63°-65° C.),used as a starting material in the above preparation, was prepared from1-chloro-4-ethoxybutan-2-one, via4-ethoxy-2-oxobutyltriphenylphosphonium chloride (m.p. 157°-160° C.), byproceeding in a similar manner to that hereinbefore described in Example3(i) for the preparation of hexanoylmethylenetriphenylphosphorane from1-chloroheptan-2-one.

(ii) Preparation of6-(7-trimethylsiloxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(ii) for the preparation of6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane,but substituting the appropriate quantity of6-(7-hydroxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonanefor the6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane usedas starting material, there was prepared6-(7-trimethylsiloxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 845 cm⁻¹, 1250 cm⁻¹.

(iii) Preparation of7-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(iii) for the preparation of7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane,but substituting the appropriate quantity of6-(7-trimethylsiloxyheptyl)-7-(5-ethoxy-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonanefor the6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared7-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 845 cm⁻¹, 1250 cm⁻¹, 3450 cm⁻¹.

(iv) Preparation of7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol

By proceeding in a similar manner to that hereinbefore described inExample 5 for the preparation of7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol, forsubstituting the appropriate quantity of7-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonanefor the7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol.Elemental analysis: Found: C, 69.2; H, 10.9%; C₂₀ H₃₆ O₄ :1/2H₂ Orequires C, 68.9; H, 10.4% ν_(max) 975 cm⁻¹, 1720 cm⁻¹, 3400 cm⁻¹.N.M.R. (approximately 10% w/v solution in deuterochloroform): triplet at1.18δ (J = 7 cycles/second), singlet at 1.3δ, multiplets at 1.0-2.8δ,3.3-3.8δ, 5.6-5.7δ.

EXAMPLE 82-(7-Acetoxyheptyl)-3-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)cyclopentanone

A solution of7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol[0.4 g; prepared as hereinbefore described in Example 7(iv)] in drypyridine (4 ml.) was treated with acetic anhydride (4 ml.) and theresulting solution was allowed to stand at ambient temperature for 3days and then diluted with water (100 ml.) with external cooling bymeans of an ice-bath. The resulting aqueous solution was extracted threetimes with chloroform, and the combined extracts were dried over sodiumsulphate. Evaporation in vacuo gave a crude product which was purifiedby preparative thin layer chromatography on silica gel using a mixtureof toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, togive2-(7-acetoxyheptyl)-3-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)cyclopentanone(0.17 g.). Elemental analysis: Found: C, 68.7; H, 10.3%; C₂₂ H₃₈ O₅requires C, 69.1; H, 10.0%. N.M.R. (approximately 10% w/v solution indeuterochloroform): multiplets at 1.0-1.9δ, 1.9-2.9δ, singlet at 2.05δ,multiplet at 3.35δ, triplet at 4.05δ, (J = 6.5 cycles/second), multipletat 5.6δ.

EXAMPLE 9 7-[5-(3-Oxo-ω-phenylalk-1-enyl)-2-oxocyclopentyl]heptanols (i)Preparation of7-[5-(3-oxo-ω-phenylalk-1-enyl)-2-oxocyclopentyl]heptanols

A suspension of6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane[1.0 g; prepared as hereinafter described in Example 9(ii)] at dilutehydrochloric acid (2N; 30 ml.) was stirred in 60°-65° C. for 1 hour. Themixture was extracted with diethyl ether and then the combined etherealextracts were washed with aqueous sodium bicarbonate solution (10% w/v)and then with water, and then dried over anhydrous magnesium sulphate.The solution was evaporated and the residue was purified by preparativethin layer chromatography on silica gel, using a mixture of diethylether, n-hexane and ethyl acetate (2:1:1 by volume) as eluant, to give7-[5-(3-oxo-3-phenylprop-1-enyl)-2-oxocyclopentyl]heptanol (0.16 g.), inthe form of a yellow oil. [Elemental analysis: Found: C, 76.9; H, 8.9%;C₂₁ H₂₈ O₅ requires C, 76.8; H, 8.6%, ν_(max) 990 cm⁻¹, 1620 cm⁻¹, 1665cm⁻¹, 3400 cm⁻¹. N.M.R. (approximately 10% w/v solution indeuterochloroform): triplet at 3.6δ (J = 6 cycles/second), multiplets at7.85-8.05δ, 7.4-7.65δ, 6.85-7.15δ, 2-2.9δ and 1.1-2.0δ].

By proceeding in a similar manner, but replacing the6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material by the appropriate quantities of6-(7-hydroxyheptyl)-7-(3-oxo-6-phenylhex-1-enyl)-1,4-dioxaspiro[4,4]nonane,6-(7-hydroxyheptyl)-7-(3-oxo-5-phenylpent-1-enyl)-1,4-dioxaspiro[4,4]nonaneand6-(7-hydroxyheptyl)-7-(3-oxo-4-phenylbut-1-enyl)-1,4-dioxaspiro[4,4]nonane[all three prepared as hereinafter described in Example 9(ii)], therewere prepared 7-[5-(3-oxo-6-phenylhex-1-enyl)-2-oxocyclopentyl]heptanol[Elemental analysis: Found: C, 77.9; H, 9.4%; C₂₄ H₃₄ O₃ requires C,77.8; H, 9.25%. ν_(max) 990 cm⁻¹, 1625 cm⁻¹, 1665 cm⁻¹, 1685 cm⁻¹, 1725cm⁻¹, 3400 cm⁻¹ ].

N.M.R. (approximately 10% w/v solution in deuterochloroform): singletsat 7.26δ and 1.79δ, doublet at 6.16δ (J = 16 cycles/second), doublet ofdoublets at 6.7δ (J = 16 and 7.5 cycles/second), triplet at 3.61δ (J = 6cycles/second), multiplets at 1.95-2.9δ and 1.1-1.95δ],7-[5-(3-oxo-5-phenylpent-1-enyl)-2-oxocyclopentyl]heptanol [Elementalanalysis: Found: C, 77.6; H, 9.2%; C₂₃ H₃₂ O₃ requires C, 77.5; H,9.05%. ν_(max) 985 cm⁻¹, 1625 cm⁻¹, 1660 cm⁻¹, 1685 cm⁻¹, 1730 cm⁻¹,3450 cm⁻¹. N.M.R. (approximately 10% w/v solution in deuterochloroform):singlet at 1.98δ, doublet at 6.16δ (J = 15.5 cycles/second), doublet ofdoublets at 6.77δ (J = 15.5 and 7.5 cycles/second), triplet at 3.61δ (J= 6 cycles/second), multiplets at 7.25δ, 2.93δ and 1.0-2.8δ], and7-[5-(3-oxo-4-phenylbut-1-enyl)-2-oxocyclopentyl]heptanol [Elementalanalysis: Found: C, 76.9; H, 9.2%; C₂₂ H₃₀ O₃ requires C, 77.15; H,8.8%. ν_(max) 990 cm⁻¹, 1625 cm⁻¹, 1670 cm⁻¹, 1690 cm⁻¹, 1730 cm⁻¹, 3450cm⁻¹ ; N.M.R. (approximately 10% w/v solution in deuterochloroform):singlet at 3.82δ, doublet at 6.20δ, (J = 15.5 cycles/second), doublet ofdoublets at 6.85δ (J = 15.5 and 7.5 cycles/second), triplet at 3.6δ (J =6 cycles/second), multiplets at 7.28δ and 1.0-2.9δ ], respectively.

(ii) Preparation of6-(7-hydroxyheptyl)-7-(3-oxo-ω-phenylalk-1-enyl)-1,4-dioxaspiro[4,4]nonanes

(a) A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane[4.0 g; prepared as hereinbefore described in Example 1(iv)] andbenzoylmethylenetriphenylphosphorane (5.6 g; prepared according to themethod of F. Ramirez and S. Dershowitz, J. Org. Chem. 1957, 22, 41) inhexamethylphosphotriamide (35 ml.) was heated on a steam bath under drynitrogen for 48 hours then poured into water (200 ml.). The mixture wasextracted with diethyl ether and the ethereal solution was washed withwater, dried over anhydrous magnesium sulphate and evaporated. Theresidue was triturated with a mixture of petroleum ether (b.p. 40°-60°C.) and diethyl ether, allowed to stand at 0° C, then filtered to removetriphenylphosphine oxide. The filtrate was evaporated to give6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane(5.5 g.) (ν_(max) 950 cm⁻¹, 985 cm⁻¹, 1615 cm⁻¹, 1660 cm⁻¹, 3380 cm⁻¹).

By proceeding in a similar manner, but substituting the appropriatequantity of 4-phenylbutanoylmethylenetriphenylphosphorane [prepared ashereinafter described in Example 9(iii)] for thebenzoylmethylenetriphenylphosphorane used as a starting material, therewas prepared6-(7-hydroxyheptyl)-7-(3-oxo-6-phenylhex-1-enyl)-1,4-dioxaspiro[4,4]nonane(ν_(max) 950 cm⁻¹, 990 cm⁻¹, 1620 cm⁻¹, 1680 cm⁻¹, 3335 cm⁻¹).

(b) A solution of dimethyl 2-oxo-4-phenylbutylphosphonate [2.5g;prepared as described hereinafter in Example 9(iv)] in anhydroustetrahydrofuran (50 ml.) was added to a stirred suspension of sodiumhydride (0.24 g.) in tetrahydrofuran (20 ml.). The mixture was stirredat room temperature in an atmosphere of nitrogen for 24 hours, thentreated dropwise with a solution of7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [2.7 g; preparedas described hereinbefore in Example 1(iv)] in tetrahydrofuran (30 ml.)and stirred for a further 2 hours in an atmosphere of nitrogen. Themixture was acidified to pH 4 by the addition of glacial acetic acid,the solvents were removed in vacuo and the residue was extracted withdiethyl ether. The ethereal solution was washed with aqueous sodiumbicarbonate solution (10% w/v) and then with water and dried overanhydrous magnesium sulphate. Evaporation of the solution gave6-(7-hydroxyheptyl)-7-(3-oxo-5-phenylpent-1-enyl)-1,4-dioxaspiro[4,4]nonane (3.9 g.), in the form of a yellow oil (ν_(max) 955 cm⁻¹, 990cm⁻¹, 1625 cm⁻¹, 1665 cm⁻¹, 1690 cm⁻¹).

By proceeding in a similar manner, but substituting the appropriatequantity of dimethyl 2-oxo-3-phenylpropylphosphonate [prepared ashereinafter described in Example 9(iv)] for the dimethyl2-oxo-4-phenylbutylphosphonate used as a starting material, there wasprepared6-(7-hydroxyheptyl)-7-(3-oxo-4-phenylbut-1-enyl)-1,4-dioxaspiro[4,4]nonane(ν_(max) 955 cm⁻¹, 990 cm⁻¹, 1625 cm⁻¹, 1665 cm⁻¹, 1685 cm⁻¹).

(iii) Preparation of 4-phenylbutanoylmethylenetriphenylphosphorane

4-Phenylbutanoyl chloride (14.7 g.) was added dropwise to a stirredsolution of diazomethane (7.5 g.) in diethyl ether (340 ml.) at 0° C.The solution was stirred in an ice bath for 1 hour further and then itwas saturated with anhydrous hydrogen chloride gas. After 1 hour at 0°C, dry nitrogen was passed through this solution, which was then pouredonto crushed ice (about 300 ml.). The ethereal layer was separated andthe aqueous phase was diluted with water (150 ml.), saturated withsodium chloride, and extracted with diethyl ether. The combined etherealsolutions were washed with water, aqueous sodium carbonate solution(2N), and then again with water, and dried over anhydrous magnesiumsulphate. The solution was evaporated and the residue was distilled, togive 1-chloro-2-oxo-5-phenylpentane (11.5 g.), b.p. 150°-151° C./10mm.Hg (Elemental analysis: C, 67.4; H, 7.1; Cl, 18.0%; C₁₁ H₁₃ C10requires C, 67.2; H, 6.7; Cl, 18.0%. ν_(max) 1455 cm⁻¹, 1500 cm⁻¹, 1725cm⁻¹).

A solution of 1-chloro-2-oxo-5-phenylpentane (6.55 g.) in dry chloroform(30 ml.) was added to a solution of triphenylphosphine (8.7 g.) in drychloroform (30 ml.) and heated at reflux in an atmosphere of drynitrogen for 4 hours. The solution was then evaporated under reducedpressure and the residual oil was triturated with a mixture of lightpetroleum ether (b.p. 40°-60° C.) and diethyl ether, to give a whitesolid. Recrystallisation of this material from a mixture ofdichloromethane and diethyl ether gave4-phenylbutanoylmethyltriphenylphosphonium chloride (11.2 g.) in theform of a white crystalline solid. m.p. 192-195° C. (Elemental analysis:C, 76.0; H, 6.2%; C₂₉ H₂₈ ClOP requires: C, 75.9; H, 6.2%; ν_(max) 1110cm⁻¹, 1445 cm⁻¹, 1490 cm⁻¹, 1695 cm⁻¹).

A solution of sodium (0.1 g.) in anhydrous ethanol (3.8 ml.) was addedto a solution of 4-phenylbutanoylmethyltriphenylphosphonium chloride(1.0 g.) in anhydrous ethanol (10 ml.) and the resulting mixture wasleft to stand at room temperature for 4 hours. The mixture wasconcentrated to half its bulk by removal of ethanol in vacuo and thendiluted with water (50 ml.) and extracted with chloroform. The combinedchloroform extracted were washed with water, dried over sodium sulphateand evaporated to dryness. The residual oil was triturated with lightpetroleum ether (b.p. 40°-60° C.) and then recrystallised fromcyclohexane, to give 4-phenylbutanoylmethylenetriphenylphosphorane (0.6g.), in the form of a white crystalline solid, m.p. 93°-95° C,(Elemental analysis: C, 82.8; H, 6.5; P, 7.6%; C₂₉ H₂₇ OP requires: C,82,4; H, 6.4; P, 7.3%; ν_(max) 1100 cm⁻¹, 1400 cm⁻¹, 1440 cm⁻¹, 1485cm⁻¹, 1540 cm⁻¹).

(iv) Preparation of dimethyl 2-oxo-ω-phenylalkylphosphonates

A solution of butyl lithium (9.6 g.) in hexane (97 ml.) and anhydrousdiethyl ether (160 ml.) was added during 20 minutes to a stirredsolution of dimethyl methylphosphonate (18.6 g.) in anhydroustetrahydrofuran (80 ml.) at -50° C, in an atmosphere of nitrogen. Thesolution was stirred for a further 15 minutes at -60° C, and then asolution of ethyl β-phenylpropionate (13.4 g.) in anhydroustetrahydrofuran (60 ml.) was added during 10 minutes at -60° C. Thissolution was stirred at -60° C, for 90 minutes and then at the ambienttemperature for 150 minutes. Glacial acetic acid (14.2 ml.) was thenadded and the solvents were evaporated off. Water (75 ml.) was added tothe gelatinous residue and then the mixture was extracted with diethylether. The ethereal extracts were washed with water, dried overanhydrous magnesium sulphate and the ether was then removed in vacuo.

The residue was distilled, to give dimethyl2-oxo-4-phenylbutylphosphonate (10.7 g.) in the form of a colourlessoil, b.p. 155°-158° C./0.1 mm.Hg. (Elemental analysis: C, 56.4; H, 6.9;P, 11.8%; C₁₂ H₁₇ O₄ P requires: C, 56.25; H, 6.7; P, 12.1%; ν_(max) 835cm⁻¹, 1035 cm⁻¹, 1180 cm⁻¹, 1260 cm⁻¹, 1455 cm⁻¹, 1710 cm⁻¹).

By proceeding in a similar manner, but replacing the ethylβ-phenylpropionate used as a starting material by the appropriatequantity of ethyl phenylacetate, there was prepared dimethyl2-oxo-3-phenylpropylphosphonate (b.p. 143°-150° C./0.1 mm.Hg; Elementalanalysis: C, 54.6; H, 6.3%; C₁₁ H₁₅ O₄ P requires: C, 54.5; H, 6.2%;ν_(max) 835 cm⁻¹, 1035 cm⁻¹, 1180 cm⁻¹, 1260 cm⁻¹, 1455 cm⁻¹, 1710cm⁻¹).

EXAMPLE 107-{5-[3-Oxo-4-(2-phenylethyl)oct-1-enyl]-2-oxocyclopentyl}heptanol (i)Preparation of7-{5-[3-oxo-4-(2-phenylethyl)oct-1-enyl]-2-oxocyclopentyl}heptanol

A solution of6-(7-hydroxyheptyl)-7-[3-oxo-4-(2-phenylethyl)oct-1-enyl]-1,4-dioxospiro[4,4]nonane[0.5 g; prepared as hereinafter described in Example 10(ii)] in aceticacid (12 ml.) and water (6 ml.) was kept at room temperature for 4 hoursthen evaporated in vacuo at a temperature below 50° C. The residue wasdissolved in diethyl ether and the ethereal solution was washed withwater, dried over magnesium sulphate and evaporated. The residue wassubjected to preparative thin layer chromatography on silica gel, usinga mixture of diethyl ether, n-hexane and ethyl acetate (2:1:1 by volume)as eluant, to give7-{5-[3-oxo-4-(2-phenylethyl)oct-1-enyl]-2-oxocyclopentyl}heptanol (0.11g.) in the form of a yellow oil [Elemental analysis: Found: C, 78.9; H,10.2%; C₂₈ H₄₂ O₃ requires C, 78.8; H, 9.9%; ν_(max) 990 cm⁻¹, 1620cm⁻¹, 1655 cm⁻¹, 1680 cm⁻¹, 1725 cm⁻¹, 3400 cm⁻¹, N.M.R. (approximately10% w/v solution in deuterochloroform): singlet at 7.21δ, doublet at6.20δ (J = 16.5 cycles/second), doublet of doublets at 6.76δ (J = 7.5and 16.5 cycles/second), triplets at 3.6δ (J = 6 cycles/second) and0.86δ, multiplets at 2.1-2.8δ, 1.05-2.1δ].

(ii) Preparation of6-(7-hydroxyheptyl)-7-[4-(2-phenylethyl)-3-oxooct-1-enyl]-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 9(ii)(b), but replacing the dimethyl2-oxo-4-phenylbutylphosphonate used as starting material by theappropriate quantity of dimethyl2-oxo-3-(2-phenylethyl)heptylphosphonate [prepared as hereinafterdescribed in Example 10(iii)], there was prepared6-(7-hydroxyheptyl)-7-[4-(2-phenylethyl)-3-oxooct-1-enyl]-1,4-dioxaspiro[4,4]nonane(ν_(max) 950 cm⁻¹, 990 cm⁻¹, 1620 cm⁻¹, 1655 cm⁻¹, 1680cm⁻¹).

(iii) Preparation of dimethyl 2-oxo-3-(2-phenylethyl)-heptylphosphonate

By proceeding in a similar manner to that hereinbefore described inExample 9(iv), but replacing the ethyl β-phenylpropionate used as astarting material by the appropriate quantity of ethyl2-(2-phenylethyl-hexanoate, there was prepared dimethyl2-oxo-3-(2-phenylethyl)heptylphosphonate (b.p. 162°-172° C./0.15 mm.Hg;Elemental analysis: C, 62.6; H, 8.6; P, 9.3%, C₁₇ H₂₇ O₄ P requires: C,62.6; H, 8.3; P, 9.5% ν_(max) 810 cm⁻¹, 1030 cm⁻¹, 1180 cm⁻¹, 1260 cm⁻¹,1455 cm⁻¹, 1700 cm⁻¹).

The ethyl 2-(2-phenylethyl)hexanoate, used as a starting material, wasprepared by heating at reflux for 18 hours a solution of2-(2-phenylethyl)hexanoic acid (17.0 g.) in anhydrous ethanol (15.5 ml)and concentrated sulphuric acid (1.5 ml.). The solution was then addedto water (150 ml.) and the oil which separated was extracted withdiethyl ether. The ethereal solution was washed successively with water,aqueous sodium carbonate solution (2N), and water, and then dried overanhydrous magnesium sulphate and evaporated. The residue was distilled,to give ethyl 2-(2-phenylethyl)hexanoate (15.25 g.) in the form of acolourless oil, b.p. 158°-160° C./7 mm.Hg (Elemental analysis: C, 77.5;H, 9.9%; C₁₆ H₂₄ O₂ requires: C, 77.4; H, 9.7%).

EXAMPLE 11 7-[2-(4-Methyl-3-oxopent-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-hydroxyheptyl)-7-(4-methyl-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 1(v), but substituting the appropriate quantity of dimethyl3-methyl-2-oxobutylphosphonate for the dimethyl3-methyl-2-oxoheptylphosphonate used as a starting material, there wasprepared6-(7-hydroxyheptyl)-7-(4-methyl-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonane,ν_(max) 3400 cm⁻¹, 1680 cm⁻¹, 1655 cm⁻¹, 1615 cm⁻¹, 1385 cm⁻¹, 1040cm⁻¹.

The dimethyl 3-methyl-2-oxobutylphosphonate (b.p. 125°-135° C./11 mm.Hg;ν_(max) 2950 cm⁻¹, 1710 cm⁻¹, 1470 cm⁻¹, 1260 cm⁻¹, 820 cm⁻¹), used as astarting material in the above preparation, was prepared by proceedingin a similar manner to that hereinbefore described in Example 9(iv) forthe preparation of dimethyl 2-oxo-4-phenylbutylphosphonate, butsubstituting the appropriate quantity of ethyl isobutyrate for the ethylβ-phenylpropionate used as starting material.

(ii) Preparation of7-[2-(4-methyl-3-oxopent-1-enyl)-5-oxocyclopentyl]heptanol

By proceeding in a similar manner to that hereinbefore described inExample 1(vi), but substituting the appropriate quantity of6-(7-hydroxyheptyl)-7-(4-methyl-3-oxopent-1-enyl)-1,4-dioxaspiro[4,4]nonanefor the6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material, there was prepared7-[2-(4-methyl-3-oxopent-1-enyl)-5-oxocyclopentyl]heptanol. Elementalanalysis: Found: C, 73.9; H, 10.8%; C₁₈ H₃₀ O₃ requires C, 73.4; H,10.3%; ν_(max) 3450 cm⁻¹, 1730 cm⁻¹, 1690 cm⁻¹, 1660 cm⁻¹, 1620 cm⁻¹,1385 cm⁻¹, 990 cm⁻¹ ; N.M.R. (approximately 10% w/v solution indeuterochloroform): septuplet at 2.88δ, multiplets at 1.8-2.8δ and1.2-1.8δ, doublet of doublets at 6.9δ (J = 7.5 and 15.5 cycles/second),triplet at 3.65δ (J = 6 cycles/second), doublets at 6.27δ (J = 15.5cycles/second) and 1.17δ (J = 7 cycles/second) and singlet at 2.1δ.

EXAMPLE 127-[2-(3-Hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol (i)Preparation of6-(7-hydroxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 9(ii), but replacing the benzoylmethylenetriphenylphosphoraneused as a starting material by the appropriate quantity ofphenoxyacetylmethylenetriphenylphosphorane, there was prepared6-(7-hydroxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane.

The phenoxyacetylmethylenetriphenylphosphorane, used as a startingmaterial, was prepared as follows:

A solution of 1-chloro-3-phenoxyacetone (6.8 g.) and triphenylphosphine(12 g.) in chloroform (16 ml.) was saturated with nitrogen and heated atreflux under nitrogen overnight. An excess of dry diethyl ether wasadded, and then the solvents were decanted from the gum that separated.The remaining solvent was removed in vacuo to give crude2-oxo-3-phenoxypropyltriphenylphosphonium chloride (10.35 g.). This wasstirred vigorously with a solution of sodium carbonate (18 g.) in water(180 ml.) for 24 hours. The solution was extracted with diethyl etherand the ethereal extracts dried over sodium sulphate. The solvent wasremoved by evaporation to givephenoxyacetylmethylenetriphenylphosphorane (5.3 g.), a sticky solid.

The 1-chloro-3-phenoxyacetone, used as a starting material, was preparedas follows:

8N Jones reagent (100 ml.) was added dropwise to a stirred solution of1-chloro-2-hydroxy-3-phenoxypropane (28.3 g.) in acetone (100 ml.)during 1 hour while maintaining the reaction temperature at 20° C. Themixture was then stirred for 4 hours, and then sufficient water wasadded to dissolve the precipitated chromium salts. The mixture wasextracted three times with diethyl ether and the combined etherealextracts were dried over sodium sulphate, concentrated under reducedpressure, dried again over sodium sulphate, and concentrated further anddistilled, to give 1-chloro-3-phenoxyacetone (13.9 g.), b.p. 150°-155°C./20 mm.Hg.

(ii) Preparation of6-(7-hydroxyheptyl)-7-(3-hydroxy-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 2(i), but replacing the6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material by the appropriate quantity of6-(7-hydroxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane,there was prepared6-(7-hydroxyheptyl)-7-(3-hydroxy-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane.

(iii) Preparation of7-[2-(3-hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol

By proceeding in a similar manner to that hereinbefore described inExample 2(ii), but replacing the6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material by the appropriate quantity of6-(7-hydroxyheptyl)-7-(3-hydroxy-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane,there was prepared7-[2-(3-hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol[Elemental analysis: Found: C, 72.9; H, 9.0%; C₂₂ H₃₂ O₄ requires C,73.2; H, 9.0%; ν_(max) 3400 cm⁻¹, 1720 cm⁻¹, 975 cm⁻¹ ; N.M.R.(approximately 10% w/v solution in deuterochloroform): multiplets at1.0-2.8δ, 3.5-4.1δ, 4.3-4.7δ, 5.6-5.9δ, 6.8-7.5δ].

EXAMPLE 137-[2-(3-Hydroxy-3-methyl-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol(i) Preparation of6-(7-trimethylsiloxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(ii), but replacing the6-(7-hydroxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane by theappropriate quantity of6-(7-hydroxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane,there was prepared6-(7-trimethylsiloxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane.

(ii) Preparation of7-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane

By proceeding in a similar manner to that hereinbefore described inExample 3(iii), but replacing the6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonaneused as starting material by the appropriate quantity of6-(7-trimethylsiloxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane,there was prepared7-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane.

(iii) Preparation of7-[2-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol

By proceeding in a similar manner to that hereinbefore described inExample 5, but replacing the7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane used as starting material by theappropriate quantity of7-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-6-(7-trimethylsiloxyheptyl)-1,4-dioxaspiro[4,4]nonane,there was prepared7-[2-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol[Elemental analysis: Found: C, 67.5; H, 8.7%; C₂₃ H₃₄ O₄ :2H₂ O requiresC, 67.3, H, 9.3%; ν_(max) 975 cm⁻¹, 1720 cm⁻¹, 3400 cm⁻¹ ; N.M.R.(approximately 10% w/v solution in deuterochloroform): multiplet at1.0-3.8δ, singlet at 1.42δ, triplet at 3.6δ, singlet at 3.85δ,multiplets at 5.7-5.9δ, 6.8-7.8δ].

The present invention includes within its scope pharmaceuticalcompositions which comprise at least one compound of the above-mentionednovel class of cyclopentane derivatives of general formula I togetherwith a pharmaceutical carrier or coating. In clinical practice the novelcompounds of the present invention will normally be administered orally,rectally, nasally, vaginally or parenterally.

The term "pharmaceutical composition", as used in the presentspecification, is meant to include compositions suitable foradministration to animals, more particularly farm animals such as horsesand cattle and other domestic animals such as dogs, as well ascompositions suitable for administration to human beings.

Solid compositions for oral administration include compressed tablets,pills, dispersible powders, and granules. In such solid compositions oneor more of the active compounds is, or are, admixed with at least oneinert diluent such as calcium carbonate, potato starch, alginic acid, orlactose. The compositions may also comprise, as is normal practice,additional substances other than inert diluents, e.g. lubricatingagents, such as magnesium stearate. Liquid compositions for oraladministration include pharamceutically-acceptable emulsions, solutions,suspensions, syrups and elixirs containing inert diluents commonly usedin the art, such as water and liquid paraffin. Besides inert diluentssuch compositions may also comprise adjuvants, such as wetting andsuspending agents, and sweetening, flavouring, perfuming and preservingagents. The compositions according to the invention, for oraladministration, also include capsules of absorbable material such asgelatin containing one or more of the active substances with or withoutthe addition of diluents or excipients.

Solid compositions for vaginal administration include pessariesformulated in manner known per se and containing one or more of theactive compounds.

Solid compositions for rectal administration include suppositoriesformulated in manner known per se and containing one or more of theactive compounds.

Preparations according to the invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or suspending media arepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,and injectable organic esters such as ethyl oleate. These compositionsmay also include adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilised, for example, by filtrationthrough a bacteria-retaining filter, by incorporation of sterilisingagents in the compositions, by irradiation, or by heating. They may alsobe manufactured in the form of sterile solid compositions, which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage for the therapeutic effect desired shall beobtained. Obviously several unit dosage forms may be administered atabout the same time. In general, the preparations should normallycontain at least 0.025% by weight of active substance when required foradministration by injection; for oral administration the preparationswill normally contain at least 0.1% by weight of active substance. Thedose employed depends upon the desired therapeutic effect, the route ofadministration and the duration of the treatment. In the adult human,the doses are generally between 0.02 and 2.0 mg. by aerosoladministration as bronchodilators, between 0.0002 and 2.0 mg./kg. bodyweight by intravenous administration, preferably by intravenous infusionat a rate of between 0.001 and 1.0 mg./kg. body weight/minute ashypotensives, between 0.001 and 0.3 mg./kg. body weight orally asinhibitors of gastric acid secretion, between 0.01 and 1.0 mg./kg. bodyweight by intravenous administration, preferably by intravenous infusionat a rate of between 0.02 and 20 μg./kg. body weight/minute asstimulators of uterine contraction, and between 1.0 and 50 μg./kg. bodyweight orally as hypocholesteraemics and hypolipidaemics, and in femalemammals between 10 and 500 μg./kg. body weight administered vaginally inthe control of oestrus. If necessary these doses may be repeated as andwhen required.

The compounds of general formula I may be administered orally asbronchodilators by any method known per se for administration byinhalation of drugs which are not themselves gaseous under normalconditions of administration. Thus, a solution of the active ingredientin a suitable pharmaceutically-acceptable solvent, for example water oraqueous ethanol, preferably in the presence of a pharmaceuticallyacceptable wetting agent, e.g. Tween 80, can be nebulized by amechanical nebulizer, for example a Wright Nebulizer, to give an aerosolof finely-divided liquid particles suitable for inhalation.Advantageously, the solution to be nebulized is diluted, solutionscontaining from 0.2 to 20 mg., and preferably 0.2 to 5.0 mg., of activeingredient per ml. of solution being particularly suitable. Aqueoussolutions may contain stabilizing agents such as sodium bisulphite andbuffering agents to give an isotonic character, e.g. sodium chloride,sodium citrate and citric acid.

The active ingredients may also be administered orally by inhalation inthe form of aerosols generated from self-propelling pharmaceuticalcompositions. Compositions suitable for this purpose may be obtained bydissolving or suspending in finely-divided form, preferably micronizedto an average particle size of less than 5 microns, the activeingredients in pharmaceutically-acceptable solvents, e.g. ethanol, whichare co-solvents assisting in dissolving the active ingredients in thevolatile liquid propellants hereinafter described, orpharmaceutically-acceptable suspending or dispersing agents, for examplealiphatic alcohols such as oleyl alcohol, and incorporating thesolutions or suspensions obtained with pharmaceutically-acceptablevolatile liquid propellants, in conventional pressurized packs which maybe made of any suitable material, e.g. metal, plastics or glass,adequate to withstand the pressures generated by the volatile propellantin the pack. Pressurized pharmaceutically-acceptable gases, such asnitrogen, may also be used as propellants. The pressurized pack ispreferably fitted with a metered valve which dispenses a controlledquantity of the self-propelling aerosol composition as a single dose.

Suitable volatile liquid propellants are known in the art and includefluorochlorinated alkanes containing from one to four, and preferablyone or two, carbon atoms, for example dichlorodifluoromethane,dichlorotetrafluoroethane, trichloromonofluoromethane,dichloromonofluoromethane and monochlorotrifluoromethane. Preferably,the vapour pressure of the volatile liquid propellant is between about25 and 65 pounds, and more especially between about 30 and 55 pounds,per square inch gauge at 21° C. As is well-known in the art, volatileliquid propellants of different vapour pressures may be mixed in varyingproportions to give a propellant having a vapour pressure appropriate tothe production of a satisfactory aerosol and suitable for the chosencontainer. For example dichlorodifluoromethane (vapour pressure 85pounds per square inch gauge at 21° C.) and dichlorotetrafluoroethane(vapour pressure 28 pounds per square inch gauge at 21° C.) may be mixedin varying proportions to give propellants having vapour pressuresintermediate between those of two constituents e.g. a mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane in the proportions38:62 respectively by weight has a vapor pressure of 53 pounds persquare inch gauge at 21° C.

The self-propelling pharmaceutical compositions may be prepared bydissolving the required quantity of active ingredient in the co-solventor combining the required quantity of active ingredient with a measuredquantity of suspending or dispersing agent. A measured quantity of thiscomposition is then placed in an open container which is to be used asthe pressurized pack. The container and its contents and then cooledbelow the boiling temperature of the volatile propellant to be used. Therequired quantity of liquid propellant, cooled below its boilingtemperature, is then added and the contents of the container mixed. Thecontainer is then sealed with the required valve fitting, withoutallowing the temperature to rise above the boiling temperature of thepropellant. The temperature of the sealed container is then allowed torise to ambient with shaking to ensure complete homogeneity of thecontents to give a pressurized pack suitable for generating aerosols forinhalation. Alternatively, the co-solvent solution of the activeingredient or combination of active ingredient and suspending ordispersing agent is placed in the open container, the container sealedwith a valve, and the liquid propellant introduced under pressure.

Means for producing self-propelling compositions for generating aerosolsfor the administration of medicaments are, for example, described indetail in U.S. Pat. Nos. 2,868,691 and 3,095,355.

Preferably, the self-propelling pharmaceutical compositions according tothe present invention contain from 0.2 to 20 mg., and more particularly0.2 to 5.0 mg., of active ingredient per ml. of solution or suspension.It is important that the pH of solutions and suspensions used, accordingto the present invention, to generate aerosols should be kept within therange 3 to 8 and preferable that they should be stored at or below 4°C., to avoid pharmacological deactivation of the active ingredient.

In carrying out the present invention, the means of producing an aerosolfor inhalation should be selected in accordance with thephysico-chemical properties of the active ingredient.

By the term "pharmaceutically-acceptable" as applied in thisspecification to solvents, wetting, suspending or dispersing agents,propellants and gases is meant solvents, suspending or dispersingagents, propellants and gases which are non-toxic when used in aerosolssuitable for inhalation therapy.

It is highly desirable that the aerosols should have a particle sizeless than about 10 microns and preferably less than 5 microns, forexample between 0.5 and 3 microns, to ensure effective distribution tovery narrow bronchioles. Preferably, administration is by means ofdevices enabling controlled quantities of the active ingredients to beadministered, for example by means of the metered valves hereinbeforementioned.

The following Examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 14

7-[2-(3-Hydroxy-3-methyloct-1-enyl)-5-oxocyclopenyl]heptanol (20 mg.)was dissolved in ethanol (10 ml.), mixed with mannitol (18.5 g.), sievedthrough a 30-mesh sieve, dried at 30° C. for 90 minutes and again sievedthrough a 30-mesh sieve. Aerosil (microfine silica) (200 mg.) was addedand the powder obtained was machine filled into one hundred No. 2 hardgelatin capsules to give capsules each containing 200 μg. of7-[2-(3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol which,after swallowing the capsules, is released into the stomach.

EXAMPLE 15

7-[2-(3-Hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (20 mg.)was dissolved in absolute ethanol (4 ml.) containing Tween 80 (1% w/v)and the solution was diluted with distilled water (36 ml.) to give asolution of the active compound suitable for a plurality of dosessuitable for intravenous injection.

We claim:
 1. A cyclopentane derivative of the formula: ##STR12## whereinR¹ is hydrogen, alkanoyl of 1 to 4 carbon atoms, or benzoyl, A isalkylene of 1 to 12 carbon atoms, Z is a direct bond or oxygen orsulphur, X is ethylene or trans-vinylene, Y is carbonyl or ##STR13##where R⁶ is hydrogen or alkyl of 1 to 4 carbon atoms and R⁷ is hydrogen,alkanoyl of 1 to 4 carbon atoms, or benzoyl, and R⁸ is phenyl ornaphthyl which is unsubstituted or substituted by halogen, alkyl of 1 to6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or trihalomethyl.
 2. Acyclopentane derivative according to claim 1 wherein A is alkylene of 1to 7 carbon atoms.
 3. A cyclopentane derivative according to claim 1wherein A is methylene, Z is oxygen and R⁸ is phenyl.
 4. A cyclopentanederivative according to claim 1 wherein Y represents a group of theformula: ##STR14## wherein R⁶ represents methyl and R⁷ is as defined inclaim
 1. 5. A cyclopentane derivative according to claim 1 wherein R⁸represents phenyl.
 6. A cyclopentane derivative according to claim 1 inwhich the group attached to the 8-position of the cyclopentane ring offormula I depicted in claim 1 is in alpha configuration and the groupattached to the 12-position of the cyclopentane ring is inbeta-configuration.
 7. A cyclopentane derivative according to claim 1which is 7-[2-(3-hydroxy-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol.8. A cyclopentane derivative according to claim 1 which is7-[2-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-5-oxocyclopentyl]heptanol.9. A cyclopentane derivative according to claim 1 which is7-[5-(3-oxo-6-phenylhex-1-enyl)-2-oxocyclopentyl]heptanol.
 10. Acyclopentane derivative according to claim 1 which is7-[5-(3-oxo-5-phenylpent-1-enyl)-2-oxocyclopentyl]heptanol.
 11. Acyclopentane derivative according to claim 1 which is7-[5-(3-oxo-4-phenylbut-1-enyl)-2-oxocyclopentyl]heptanol.
 12. Acyclopentane derivative according to claim 1 which is7-{5-[3-oxo-4-(2-phenylethyl)oct-1-enyl]-2-oxocyclopentyl}heptanol.